ABSTRACT ? CANCER METABOLISM AND SIGNALING NETWORKS PROGRAM The long-term goal of the Cancer Metabolism and Signaling Networks (CMSN) program is to unravel the mechanisms and signaling networks in normal and cancer cells that govern their ability to either survive or to undergo various forms of death when stressed (as a consequence of either the inherent requirements of uncontrolled cancer cell growth, or chemotherapy). The program includes 10 investigators, including 5 adjuncts, with strong expertise in autophagy and cell death, metabolic signaling, and structural and chemical biology, who work in a highly interactive approach with the ultimate goal of efficient translation of our discoveries into more selective and efficacious therapies. The program consists of three well-defined and highly synergistic themes: (1) Cancer Metabolism, (2) Nutrient Sensing, and (3) Cell Death and Survival. These themes are conceptually linked, with metabolic and protein stress in cancer cells closely interconnected to cell survival, cell death, and autophagy. Exploiting these and other signaling pathways through chemical biology is expected to lead to new therapies for cancer. The program has reinforced its cancer focus, as suggested by the previous review, and fosters collaborations among its members through joint lab meetings, monthly program meetings, retreats, and mentoring of junior faculty, postdoctoral fellows, and students. As documented by our current annual direct cancer-related funding of $7.3M with $4.6M from NCI (63%), the program has been very productive during this period. Program members currently lead or participate in a total of 28 grants including 19 R01s (11 from NCI), and multiple NExT (NCI) projects. Members have authored 254 cancer-relevant papers (between 2014 and 2019), of which 24% were collaborative (13% intra-programmatic and 11% inter-programmatic). Of these, 29 were published in 2018, 21% intra-programmatic and 7% inter-programmatic. A central goal for the program for the next five years is to further enhance interactions among members that allow us to address fundamental questions in the area of cancer metabolism and cell survival. We plan to extend our expertise in these areas by recruiting at least one faculty in cancer metabolism and, in collaboration with TMCI, another faculty with interest in metabolism in the tumor stroma, an emerging field at the interface of metabolism, inflammation, and the tumor microenvironment. Another faculty member will be recruited in the area of autophagy in mouse cancer models. Our ability to translate our findings into innovative therapies will benefit greatly from the presence of program members with outstanding expertise in structural and chemical biology and the rational design of drugs based on structural data, combined with the capabilities of the Conrad Prebys Center for Chemical Genomics in medicinal chemistry and high-throughput screening.